The folic acid antimetabolites aminopterin and amethopterin (also known as 10-methylaminopterin or methotrexate) are antineoplastic agents. These compounds inhibit enzymatic conversions involving metabolic derivatives of folic acid. Amethopterin, for example, inhibits dihydrofolate reductase (DHFR), an enzyme necessary for the regeneration of tetrahydrofolate from dihydrofolate which is formed during the conversion of 2-deoxyuridylate to thymidylate by the enzyme thymidylate synthetase.
Other derivatives of folic acid and aminopterin have been synthesized and tested as antimetabolites. Among these are compounds in which a methylene or methylidene group occupies a position in the molecule normally occupied by an imino or nitrilo group, respectively. These derivatives have varying degrees of antimetabolic activity. 10-Deazaaminopterin is highly active (Sirotnak et al., Cancer Treat. Rep. 62: 1047 (1978)) and 5-deazaaminopterin has activity similar to that of amethopterin (Taylor et al., J. Org. Chem., 48: 4842 (1983)). 8,10-Dideazaaminopterin is reported to be antimetabolically active (U.S. Pat. No. 4,460,591) and 5,8,10-trideazaaminopterin exhibits activity against mouse L1210 leukemia (Yan et al., J. Heterocycl. Chem., 16: 541 (1979)). 10-Deazafolic acid, on the other hand, shows no significant activity (Struck et al., J. Med. Chem., 14: 693 (1971)) and 5-deazafolic acid is only weakly cytotoxic. 8,10-Dideazafolic acid is only marginally effective as a dihydrofolate reductase inhibitor (De Graw et al., "Chemistry and Biology of Pteridines", Elsevier, 229 (1979)) and 5,8,10-trideazafolic acid also shows only marginal activity against mouse L1210 leukemia (Oatis et al., J. Med. Chem., 20: 1393 (1977)). 5,10-Dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin, and the corresponding 5,10-dideazafolic acid derivatives are reported by Taylor et al., J. Med. Chem., 28, No. 7: 914 (1985).
Additional derivatives of folic acid and aminopterin include: 10-oxafolic acid and 7,8-dihydro-10-oxafolic acid which are not effective inhibitors of DCM resistant Lactobacillus casei dihydrofolate reductase; 10-oxaaminopterin and 7,8-dihydro-10-thiofolic acid, which are potent DHFR inhibitors (Nair et al., J. Med. Chem., 19, No. 6: 825 (1976)); 10-thiafolic acid, a moderate DHFR inhibitor; and a very potent dihydrofolate reductase inhibitor, 10-thiaaminopterin (Kim et al., J. Med. Chem., 18, No. 8: 776 (1975)).
This invention provides novel folic acid derivatives, their composition and use. In particular, this invention concerns 5-deaza-10-oxo- and 5-deaza-10-thio-5,6,7,8-tetrahydrofolic acid, intermediates for their preparation, pharmaceutical formulations containing the named compounds, and their use for the treatment of susceptible neoplasms.